Although novel therapeutic approaches have been developed for treating follicular lymphomas (FL), the overall survival has not yet been significantly improved. The anti-CD20 monoclonal antibody rituximab, has significant, albeit limited activity as a single agent for treatment of FL. Immunostimulatory DNA oligonucleotides (ISS) have pleotropic effects, including enhancement of antigen presentation and co-stimulatory molecule expression, stimulation of dendritic cell maturation, and induction of cytokines and augmented antibody-dependent cell-mediated cytotoxicity. Through effects on both adaptive and innate immunity, we hypothesize ISS may synergize with rituximab. Given a favorable safety profile, and evidence of biologic activity in a phase I study of ISS (1018) with rituximab, we plan to evaluate rituximab with 1018 ISS in a phase II study for relapsed FL patients. We propose three aims. First, to undertake a clinical trial of 1018 ISS with rituximab for patients with relapsed FL. Second, to investigate in situ effects of the combination 1018 ISS and rituximab on effector cells and the tumor microenvironment. Third, to investigate effects of 1018 ISS and rituximab on the immune response in vitro. This study is a novel approach to treating FL, where augmenting antigen presentation and effector cells may lead to enhanced cytotoxic effects of rituximab and induce anti-tumor immunity.